Peptides influencing diuresis and natriuresis, a process for their preparation, agents containing them, and their use

Abstract

The invention relates to peptides of the formula R.sup.N --L--N--B.sup.2 --R.sup.C (I) in which R N denotes an acyl radical, L denotes a radical of a lipophilic, neutral α-amino acid, N denotes a radical of an neutral α-amino acid, B 2 denotes the radical of a basic α-amino acid, and R C denotes an amido radical; a process for their preparation, agents containing these peptides, and their use.

We claim: 
     
       1. A compound of formula I   R.sup.N --L--N--B.sup.2 --R.sup.6                          (I)     in which   R N  represents a radical of the formula II; ##STR4## R 2  represents hydrogen or a radical of the formula R--[A] n  --NH--;   R 3  denotes amino, guanidino, (C 1  -C 3 )-alkylamino or di-(C 1  -C 3 )-alkylamino;   m denotes an integer from 1 to 6;   A represents a radical of the formula --NH--CR 4  R 5  --CO--;   R denotes hydrogen, (C 1  -C 6 )-alkanoyl, (C 7  -C 11 )-aroyl, in which the aromatic moiety is unsubstituted or mono- or disubstituted by (C 1  -C 4 )-alkyl, (C 1  -C 4 )-alkoxy, (C 1  -C 4 )-alkylthio, halogen, carbamoyl, (C 1  -C 4 )-alkoxycarbonyl and/or sulfamoyl, or is monosubstituted by methylenedioxy, or denotes (C 5  -C 7 )-cycloalkyl-(C 1  -C 3 )-alkanoyl or (C 6  -C 14 )-aryl-(C 1  -C 3 )-alkanoyl, where a --CH 2  group in the radicals where R is not a hydrogen can be replaced by --O-- or --S--;   n is 0 or, if p=1, n represents 1;   R 4  and R 5  are identical or different and denote hydrogen, (C 1  -C 6 )-alkyl or (C 7  -C 11 )-aralkanoyl;   L represents Pro, D-Pro or a radical of the formula --NH--CH(R 6 )--CO--;   R 6  denotes (C 1  -C 6 )-alkyl which is unsubstituted or monosubstituted by hydroxyl, (C 1  -C 6 )-alkoxy, (C 1  -C 6 )-alkoxy-carbonyl, carbamoyl or R-NH, R being as defined above but cannot be hydrogen, or denotes (C 7  -C 11 )-aralkyl which is unsubstituted or monosubstituted on the aromatic ring by (C 1  -C 6 )-alkoxy, or denotes 3-indolymethyl;   N represents Pro, D-Pro or a radical of the formula --NH--CH(R 7 )--CO--;   R 7  denotes (C 1  -C 6 )-alkyl which is unsubstituted or monosubstituted by hydroxyl, (C 1  -C 6 )-alkoxy, (C 1  -C 6 )-alkoxycarbonyl, carbamoyl or R-NH, R being as defined above but cannot be hydrogen, or denotes (C 7  -C 11 )-aralkyl which is unsubstituted or monosubstituted on the aromatic ring by (C 1  -C 6 )-alkoxy, or denotes 3-indolymethyl;   B 2  represents Arg, D-Arg, Lys or D-Lys;   R C  represents a radical of the formula --NR 9  --CH(R 8 )--(CO) p  --R 1  ;   R 8  is defined as R 7 , with CH, CH 2  or CH 3  radicals which are present in the β-position with respect to --NH-- optionally being monohydroxylated, and   R 9  denotes hydrogen; or   R 8  and R 9  together denote --[CH 2  ] 3  -- or [CH 2  ] 4  ;   p is 0 or 1   R 1  represents hydrogen, hydroxyl or (C 1  -C 6 )-alkoxy in the case of p=0;   R 1  represents OR 10  or NR 10  R 11  in the case of p=1; and   R 10  and R 11  are identical or different and denote hydrogen, (C 1  -C 6 )-alkyl or (C 7  -C 11 )-aralkyl; or NR 10  R 11  represents pyrrolidino, piperidino or morpholino; or   p is 1, or if n=0, p represents 0;   R and R 1  together denote a bond, and the other radicals are as defined above, and its physiologically tolerated salts.     
     
     
       2. A compound of the formula I as claimed in claim 1, in which L represents the radical of isoleucine, valine, threonine, serine, O-(C 1  -C 9 )-alkylthreonine, O-(C 1  -C 9 )-alkylserine, leucine, proline or of the ω-(C 1  -C 6 )-alkyl ester, preferably tert.butyl ester, of glutamic acid or aspartic acid;   N represents the radical of valine, isoleucine, leucine, phenylalanine, tryptophan, tyrosine which is optionally O-(C 1  -C 6 )-alkylated, glutamine, asparagine, γ-(C 1  -C 6 )-alkyl glutamate or β-(C 1  -C 6 )-alkyl aspartate or ε-acyl-lysine, and   B 2  denotes Arg, D-Arg, Lys or D-Lys, and its physiologically tolerated salts.   
     
     
       3. A compound of the formula I as claimed in claim 1, in which p is 1 and R and R 1  together represent a bond, and its physiologically tolerated salts. 
     
     
       4. A compound of the formula I as claimed in claim 1, in which R and R 1  do not together represent a bond, and its physiologically tolerated salts. 
     
     
       5. A method for the treatment of disturbances of diuresis, which comprises administration of an effective amount of a compound of the formula I as claimed in claim 1, or of its physiologically tolerated salt. 
     
     
       6. A method for the treatment of hypertension and dropsy, which comprises administration of an effective amount of a compound of the formula I as claimed in claim 1, or of its physiologically tolerated salt. 
     
     
       7. A method for the treatment of polyuria or diabetes insipidus, which comprises administration of an effective amount of a compound of the formula I as claimed in claim 1, or of its physiologically tolerated salt. 
     
     
       8. A pharmaceutical formulation for the treatment of disturbances of diuresis, hypertension and dropsy, polyuria or diabetes insipidus comprising an effective amount of the compound of the formula I as claimed in claim 1, or of its physiologically tolerated salt, and a pharmaceutically acceptable vehicle. 
     
     
       9. A compound according to the formula cyclo-(Gly-Arg-Ile-Phe-Arg-Ile). 
     
     
       10. A compound according to the formula cyclo-(Gly-Arg-Ile-Leu-Arg-Ile). 
     
     
       11. A compound according to the formula cyclo-(D-Arg-Ile-D-Leu-Arg-Ile). 
     
     
       12. A compound according to the formula cyclo-(D-Arg-Ile-D-Leu-Arg-Ile) diacetate. 
     
     
       13. A compound according to the formula cyclo-(D-Arg-Ile-D-Leu-Arg-D-Val).